Rapid Magnetomotive Thrombolysis for Stroke

快速磁动力溶栓治疗中风

• 批准号: 8833670
• 负责人: Francis Milton Creighton
• 金额: $ 21.88万
• 依托单位: PULSE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2015-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833670
• 关键词: Accident and Emergency department; Acute; Address; Algorithmic Software; Algorithms; Alteplase; American; Animals; Automobile Driving; Biochemical; Biological Assay; Biological Availability; Blood coagulation; Blood flow; Brain; Caring; Cessation of life; Classification; Clinical; Clinical Trials; Coagulation Process; Collection; Cytolysis; Data; Devices; Diffuse; Diffusion; Dose; Dose-Rate; Effectiveness; Enrollment; FDA approved; Failure; Fibrinolytic Agents; Futility; Goals; Guidelines; Hemorrhage; Human; Hypotension; In Vitro; International; Intravenous; Investigation; Ischemic Stroke; Kinetics; Knowledge; Lead; Legal patent; Liquid substance; Location; Magnetism; Measures; Modeling; Neurologic; Neurological outcome; Outcome; Performance; Pharmaceutical Preparations; Phase; Physiologic pulse; Pilot Projects; Population; Pre-Clinical Model; Preparation; Procedures; Recommendation; Recovery; Reperfusion Therapy; Research; Risk; Safety; Site; Small Business Innovation Research Grant; Solutions; Stroke; Surface; System; Technology; Testing; Therapeutic; Thrombolytic Therapy; Time; Toxic effect; Uncertainty; United States; Visual; base; biomaterial compatibility; brain tissue; cerebral artery; commercialization; cost; design; disability; experience; improved; intravenous administration; magnetite ferrosoferric oxide; meetings; minimally invasive; particle; pre-clinical; preclinical efficacy; preclinical safety; preclinical study; prevent; prototype; public health relevance; standard of care; success; thrombolysis; treatment effect

DESCRIPTION (provided by applicant): Acute ischemic stroke (AIS) is the result of a blood clot in a cerebral artery. It remains a leading killer and the leading cause of long-term disabilit, annually impacting over 700,000 Americans [10]. Because brain tissue rapidly dies, time to reperfusion is critical in both preventing death and improving neurological outcomes. While current annual costs related to ischemic stroke are high in the United States (US), they are projected to increase from $72B in 2013 to $183B by 2030 [14]. Intravenous (IV) administration of tissue plasminogen activator (tPA) remains the standard of care for AIS [15], despite a small ~10% chance for a full recovery and a >65% chance of death or severe disability [16]. While tPA has been proven to offer statistically-significant benefits, albeit low, in AIS [11] [12] [13], the dose- dependent bleeding associated with tPA has resulted in a low ~8% administration rate in the US. As a result, a large majority of stroke victims are greatly underserved despite efforts to improve standards of care. Due to poor fluid dynamics, the effectiveness of all thrombolytic drugs is because of their inability to rapidly diffuse to a clot in the occluded vessel [17]. Pulse Therapeutics, Inc.'s (PTI's) patented and clinically- investigated technology has overcome this limitation in a way that dramatically accelerates tPA delivery to a clot by using non-tPA-attached magnetite particles controlled by an external magnet. This technology is deployed in the emergency department after the baseline CT. However, by attaching the FDA-approved drug tPA to PTI's magnetite particles, the technology promises faster clot lysis (driving better neurological outcomes) at a substantially lower tPA dose (allowing expansion to nearly all ischemic strokes). PTI's objective is to demonstrate dramatic improvements in thrombolysis by attaching tPA to the company's magnetic particles. In Phase I, PTI will attempt to 1) develop optimal magnetite particles with the best- performing tPA coating conjugated to the surface, 2) collect data on the candidate particle's clot lysis rate and proper dosing in vitro, 3) optimize a software algorithm for automated particle collection, and 4) conduct a pre- submission meeting with the FDA. For Phase II, PTI will 5) modify an existing PTI magnet system suitable for use in pre-clinical animal studies, 6) identify the best tPA-coated particle from safety and efficacy GLP preclinical studies, and 7) assemble a data package in preparation for a subsequent FDA IDE submission. The proposed technology has dramatic implications for the treatment of AIS. By delivering tPA directly to the clot's surface via attachment to magnetic particles, clot lysis willto occur faster and result in better neurological outcomes, while drug-related toxicity effects may be eliminated, thereby expanding thrombolytic therapy from the ~30% maximum stroke victims eligible today, to potentially all ischemic stroke victims.

描述（由申请人提供）：急性缺血性中风（AIS）是脑动脉中血凝块的结果。它仍然是领先的杀手和长期不庇护的主要原因，每年都会影响700,000多名美国人[10]。由于脑组织迅速死亡，因此再灌注的时间对于预防死亡和改善神经系统结局至关重要。尽管与缺血性中风有关的当前年度成本在美国很高（美国），但预计到2030年，它们的增加率将从2013年的72B美元增加到183B美元[14]。静脉内（IV）组织纤溶酶原激活剂（TPA）的给药仍然是AIS的护理标准[15]，尽管大约10％的机会完全康复了，并且> 65％的死亡或严重残疾机会> 65％[16]。虽然已证明TPA可以在AIS [11] [12] [13]中提供统计学上很重要的好处，但 与TPA相关的剂量依赖性出血导致美国的管理率低约8％。结果，尽管努力提高了护理标准，但绝大多数中风受害者都在服务不足。由于流体动力学不良，所有溶栓药的有效性是因为它们无法快速扩散到闭塞血管中的凝块[17]。脉冲 Therapeutics，Inc。（PTI）获得了专利和临床研究的技术，通过使用由外部磁铁控制的非TPA附着的磁铁矿颗粒，以极大地加速TPA到凝块的方式克服了这一局限性。基线CT之后，该技术部署在急诊科。但是，通过将FDA批准的药物TPA连接到PTI的磁铁矿颗粒上，该技术有望以较低的TPA剂量（允许将几乎所有缺血性中风扩展）更快地溶解（推动更好的神经学结果）。 PTI的目标是通过将TPA连接到公司的磁性颗粒来证明溶栓的改善。在第一阶段，PTI将尝试1）开发最佳的磁铁矿颗粒，具有结合到表面的最佳性能TPA涂层，2）收集有关候选粒子的凝块裂解速率的数据，并在体外进行适当的给药，3）优化软件算法，用于自动化粒子的收集，以及4）在与FDA相交的情况下，进行预先提交。对于II期，PTI将5）修改适用于临床前动物研究中的现有PTI磁铁系统，6）从安全性和有效性GLP临床前研究中确定最佳的TPA涂层粒子，以及7）7）在准备后续FDA IDE列出的准备工作中组装数据包。提出的技术对AIS的治疗具有巨大的影响。通过将TPA直接通过附着在磁性颗粒上传递到凝块的表面，凝块裂解愿意的发生速度更快并导致更好的神经系统结果，而与药物相关的毒性效应可能会消除，从而从当今有可能有资格的最大性感受害者扩大了溶栓疗法，从而扩大了所有的最大性疾病受害者，从而使所有缺血性的Strouke受害者都具有潜在的所有缺血性Stroke受害者。